The applicants demonstrated that functioning foreign genes encoding both intracellular and secreted protein can be introduced into the lungs of mice by either intravenous of intratracheal injection of DNA complexes to specially synthesized cationic small liposomes (lipofection). In this application, the applicants propose to determine the specificity, toxicity and efficacy of this method of gene therapy in animals. They will concentrate on methods which ensure transient expression of the introduced genes because such methods may be readily applied to humans and may also be particularly relevant to acute diseases of the lungs where both periods at risk and duration of the disease are short. Using plasmid constructs encoding commonly used reporter genes, they will determine the toxicity, dose-response relationships, duration of expression and organ and cell specificity of transection and expression of genes introduced into the lung of mice by lipofection. They will construct vectors in which reporter genes are driven by promoter sequences which respond to either glucocorticoids or zinc and determine in mice whether in vivo expression of the transfected gene can be regulated by administration of Zn or dexamethasone to the animals. The applicants will develop expression vectors containing DNA encoding either human Mn superoxide dismutase or alpha-1 antitrypsin which result in increased production of these proteins in the lungs of lipofected mice and determine whether mice transfected with these vectors are resistant to either pulmonary oxygen toxicity or endotoxin induced lung injury. In chronically instrumented sheep, they will measure the physiological effects of either intravenous or intratracheal administration of DNA-liposome complexes and determine the duration and specificity of expression of transfected genes. These studies are done with the eventual goal of clinical application of transient gene therapy to the lungs. Such an accomplishment would greatly expand the potential for gene therapy to include a host of acute diseases of the lungs including the adult respiratory distress syndrome (ARDS).